2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses

ABSTRACT

The invention concerns 2-oxo-1-pyrrolidine derivatives and a process for preparing them and their uses. The invention also concerns a process for preparing α-ethyl-2-oxo-1-pyrrolidine acetamide derivatives from unsaturated 2-oxo-1-pyrrolidine derivatives. Particularly the invention concerns novel intermediates and their use in methods for the preparation of S-α-ethyl-2-oxo-1-pyrrolidine acetamide.

This application is a 371 of PCT/EP01//01956 Feb. 21, 2001.

The invention concerns 2-oxo-1-pyrrolidine derivatives and a process forpreparing them and their uses. The invention also concerns a process forpreparing α-ethyl-2-oxo-1-pyrrolidine acetamide derivatives fromunsaturated 2-oxo-1-pyrrolidine derivatives.

Particularly the invention concerns novel intermediates and their use inmethods for the preparation of (S)-(−)-α-ethyl-2-oxo-1-pyrrolidineacetamide, which is referred under the International Nonproprietary Nameof Levetiracetam, its dextrorotatory enantiomer and related compounds.Levetiracetam is shown as having the following structure:

Levetiracetam, a laevorotary compound is disclosed as a protective agentfor the treatment and the prevention of hypoxic and ischemic typeaggressions of the central nervous system in the European patent No.162036. This compound is also effective in the treatment of epilepsy, atherapeutic indication for which it has been demonstrated that itsdextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidine acetamidecompletely lacks activity (A. J. GOWER et al., Eur. J. Pharmacol., 222,(1992), 193-203). Finally, in the European patent application No. 0 645139 this compound has been disclosed for its axiolytic activity.

The asymmetric carbon atom carries a hydrogen atom (not shown)positioned above the plane of the paper. The preparation ofLevetiracetam has been described in the European patent No. 0162 036 andin the British patent No. 2 225 322, both of which are assigned to theassignee of the present invention. The preparation of the dextrorotatoryenantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidine acetamide has beendescribed in the European patent No. 0165 919. Nevertheless, theseapproaches do not fully satisfy the requirements for an industrialprocess. Therefore, a new approach has been developed via the asymmetrichydrogenation of new precursors.

In one aspect, the invention provides a compound having the generalformula (A) and pharmaceutically acceptable salts thereof,

wherein X is —CONR⁵R⁶ or —COOR⁷ or —COR⁸ or CN;

R¹ is hydrogen or alkyl, aryl, heterocycloalkyl, heteroaryl, halogen,hydroxy, amino, nitro, cyano;

R², R³, R⁴, are the same or different and each is independently hydrogenor halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid,sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl,arylsulfmyl, alkylthio, arylthio, alkyl, alkoxy, oxyester, oxyamido,aryl, arylamino, axyloxy, heterocycloalkyl, heteroaryl, vinyl;

R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycloalkyl,heteroaryl, alkylthio, arylthio.

The term alkyl as used herein, includes saturated monovalent hydrocarbonradicals having straight, branched or cyclic moieties or combinationsthereof and contains 1-20 carbon atoms, preferably 1-5 carbon atoms. Thealkyl group may optionally be substituted by 1 to 5 substituentsindependently selected from the group consisting halogen, hydroxy,thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl,alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide,alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl,arylsulfinyl, alkylthio, arylthio, oxyester, oxyamido, heterocycloalkyl,heteroaryl, vinyl, (C1-C5)alkoxy, (C6-C10)aryloxy, (C6-C10)aryl.Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least agroup selected from halogen, hydroxy, thiol, amino, nitro, cyano, suchas trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

The term “heterocycloalkyl”, as used herein, represents an“(C1-C6)cycloalkyl” as defined above, having at least one O, S and/or Natom interrupting the carbocyclic ring structure such astetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl,morpholino and pyrrolidinyl groups or the same substituted by at least agroup selected from halogen, hydroxy, thiol, amino, nitro, cyano.

The term “alkoxy”, as used herein includes —O-alkyl groups wherein“alkyl” is defined above. Preferred alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or thesame substituted by at least a halo group such as trifluoromethyl,trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

The term “alkylthio” as used herein, includes Bakyl groups wherein“alkyl” is defined above. Preferred alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or thesame substituted by at least a halo group, such as trifluoromethyl,trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

The term “alkylamino” as used herein, includes —NHalkyl or —N(alkyl)₂groups wherein “alkyl” is defined above. Preferred alkyl groups aremethyl, ethyl, n-propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.

The term “aryl” as used herein, includes an organic radical derived froman aromatic hydrocarbon by removal of one hydrogen, such as phenyl,phenoxy, naphthyl, arylalkyl, benzyl, optionally substituted by 1 to 5substituents independently selected from the group halogen, hydroxy,thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl,alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide,alkylsulfonyl, alkoxycarbonyl, alkylsulfinyl, alkylthio, oxyester,oxyamido, aryl, (C1-C6)alkoxy, (C6-C10)aryloxy and (C1-C6)alkyl. Thearyl radical consists of 1-3 rings preferably one ring and contains 2-30carbon atoms preferably 6-10 carbon atoms. Preferred aryl groups are,phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, naphthyl,benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl,2-phenylethyl.

The term “arylanino” as used herein, includes —NHaryl or —N(aryl)₂groups wherein “aryl” is defined above. Preferred aryl groups are,phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl,halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

The term “aryloxy”, as used herein, includes —O-aryl groups wherein“aryl” is defined as above. Preferred aryl groups are, phenyl,halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

The term “arylthio”, as used herein, includes aryl groups wherein “aryl”is defined as above. Preferred aryl groups are, phenyl, halophenyl,cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The teem “cyano”, as used herein, represents a group of the formula —CN.

The term “ritro”, as used herein, represents a group of the formula—NO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “heteroaryl”, as used herein, unless otherwise indicated,represents an “aryl” as defined above, having at least one O, S and/or Ninterrupting the carbocyclic ring structure, such as pyridyl, furyl,pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl,pyrazinyl, pyiimidyl, quinolyl, isoquinolyl, isobenzofuryl,benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, or benzoxazolyl,optionally substituted by 1 to 5 substituents independently selectedfrom the group consisting hydroxy, halogen, thiol, amino, nitro, cyano,acyl, acyloxy, sulfonyl, sulfmyl, alkylamino, carboxy, ester, ether,amido, sulfonic acid, sulfonamide, alkylsulfonyl, alkoxycarbonyl,oxyester, oxyamido, alkoxycarbonyl, (C1-C5)alkoxy, and (C1-C5)alkyl.

The term “arylalkyl” as used herein represents a group of the formulaaryl-(C1-C4 alkyl)-. Preferred arylalkyl groups are, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl, diphenylmethyl,(4-methoxyphenyl)diphenylmethyl.

The term “acyl” as used herein, represents a radical of carboxylic acidand thus includes groups of the formula alky-CO—, aryl-CO—,heteroaryl-CO—, arylalkyl —CO—, wherein the various hydrocarbon radicalsare as defined in this section. Preferred alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least a halo group. Preferred aryl groupsare, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl,benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl,2-phenylethyl.

The term “oxyacyl” as used herein, represents a radical of carboxylicacid and thus includes groups of the formula alky-CO—O—, aryl-CO—O—,heteroaryl-CO—O—, arylalkyl-CO—O, wherein the various hydrocarbonradicals are as defined in this section. Preferred alky and aryl groupsare the same as those defined for the acyl group.

The term “sulfonyl” represents a group of the formula —SO₂-alkyl or—SO₂-aryl wherein “alkyl” and “aryl” are defined above. Preferred alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl,methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl,nitrobenzyl, 2-phenylethyl.

The term “sulfmyl” represents a group of the formula —SO-alkyl or—SO-aryl wherein “allyl” and “aryl” are defined above. Preferred alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl,methoxyphenyl. benzyl, halobenzyl, cyanobenzyl, methoxybenzyl,nitrobenzyl, 2-phenylethyl.

The term “ester” means a group of formula —COO-alkyl, or —COO-arylwherein “alkyl” and “aryl” are defined above. Preferred alkyl groups aremethyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl,methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl,nitrobenzyl, 2-phenylethyl.

The term “oxyester” means a group of formula —COO-alkyl, or —COO-arylwherein “alkyl” and “aryl” are defined above. Preferred alkyl groups aremethyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl,methoxyphenyl benzyl, halobenzyl, cyanobenzyl, methoxybenzyl,nitrobenzyl, 2-phenylethyl.

The term “ether” means a group of formula alkyl-O-alkyl or alkyl-O-arylor aryl-O-aryl wherein “alkyl” and “aryl” are defined above. Preferredalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least ahalo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl,nitrophenyl, methoxyphenyl benzyl, halobenzyl, cyanobenzyl,methoxybenzyl, nitrobenzyl, 2-phenylethyl.

The term “amido” means a group of formula —CONH₂ or —CONHalkyl or—CON(alkyl)₂ or —CONHaryl or —CON(aryl)₂ wherein “alkyl” and “aryl” aredefined above. Preferably alkyl has 1-4 carbon atoms and aryl has 6-10carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the samesubstituted by at least a halo group. Preferred aryl groups are, phenyl,halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

The term “oxyamido” “means a group of formula —O—CONH2 or —O—CONHalkylor —O—CON(alkyl)2 or —O-CONHaryl or —CON(aryl)2 wherein alkyl” and“aryl” are defined above. Preferably alkyl has 1-5 carbon atoms and arylhas 6-8 carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the samesubstituted by at least a halo group. Preferred aryl groups are, phenyl,halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

Preferably R¹ is methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least ahalogen group such as trifluoromethyl trichloromethyl,2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

Preferably R², R³ and R⁴ are independently hydrogen or halogen ormethyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo groupsuch as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

Preferably R⁵ and R⁶ are independently hydrogen, methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl.

Preferably R⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl orthe same substituted by at least a halo group such as trifluoromethyl,chlorophenyl.

Preferably R⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the samesubstituted by at least a halo group such as trifluoromethyl,chlorobenzyl or where X is —CN.

Unless otherwise stated, references herein to the compounds of generalformula (A) either individually or collectively are intended to includegeometrical isomers i.e. both Z (Zusammen) and E (Entgegen) isomers andmixtures thereof (racemates).

With respect to the asymmetric hydrogenation process described below,the best results have been obtained for the Z (Zusammen) and E(Entgegen) isomers of the compounds of formula (A) where R¹ is methyl,R² and R⁴ are H and X is —CONH₂ or —COOMe or —COOEt or —COOH. Withinthis group, compounds wherein R³ is hydrogen, alkyl (especially propyl)or haloalkenyl (especially difluorovinyl) are particularly well suited.

An aspect of the invention concerns a process for preparing the compoundhaving a general formula (A). This process includes the followingreactions:

Compounds having a general formula (A), where X is —CONR⁵R⁶ or —COOR⁷ or—COR⁸ or CN, may conveniently be made by reaction of an α-ketocarboxylicacid derivative of general formula (C) where R¹ and X are describedabove, with a pyrrolidinone of general formula (D) where R², R³, R⁴ aredescribed above, according to the following scheme (1).

Compounds having a general formula (A) where X is —COOR⁷ mayconveniently be made by reaction of an α-ketocarboxylic acid derivativeof general formula (C′) where X is —COOR⁷ with a pyrrolidinone ofgeneral formula (D) according to the following scheme (2).

Suitable reaction conditions involve use of toluene under reflux. In theresulting compound (A), R⁷ may readily be converted from H to alkyl orfrom alkyl to H.

Derivatives of general formula (C) or (C′) and pyrrolidones of generalformula (D) are well known by the man of the art and can be preparedaccording to syntheses referred to in the literature, such as in“Handbook of Heterocyclic Chemistry” by A. Katrisky, Pergamon, 1985(Chapter 4.) and in “Comprehensive Heterocyclic Chemistry” by A.Katrisky & C. W. Rees, Pergamon, 1984 (Volume 4, Chapters 3.03 & 3.06).

Compounds of general formula (A) where X is —CONH₂ or —CONR⁵R⁶ mayconveniently be prepared by conversion of the corresponding acid(compound of formula (A) where X is CO₂H) to the acid chloride withsubsequent ammonolysis or reaction with a primary or secondary amine ofthe general formula HNR⁵R⁶. The following two schemes (3 and 4) describesuch a process.

These reactions are preferably performed using PCl₅ to give an acidchloride followed by anhydrous ammonia or primary or secondary amine ofthe formula HNR⁵R⁶ to give the desired enamide amide.

Compounds of general formula (A) where X is —COOR⁷ may conveniently bemade by conversion of the corresponding acid (compound (A) where X isCOOH) obtained by Scheme (2) to the acid chloride with subsequentalcoholysis with the compound of formula R⁷—OH (alcohol) where R⁷ isdefined above. (see Scheme 5)

These reactions are preferably performed using PCl₅ to give an acidchloride followed by alcoholysis with R⁷—OH to give the desired ester.

The conditions of the above reactions are well known by the man skilledin the art.

In another aspect the invention concerns the use of compounds of formula(A) as synthesis intermediates.

The compound of formula (A) where X is —CONH₂ is of particular interest,as catalytic hydrogenation of this compound leads directly toLevetiracetam. Both the Z (Zusammen) and E (Entgegen) isomers of thesecompounds have been shown to undergo rapid and selective asymmetrichydrogenation to either enantiomer of the desired product. Therepresentation of the bond joining the group R¹ to the molecule denoteseither a Z isomer or an E isomer As a particular example, the use ofcompounds (A) for the synthesis of compounds (B) may be illustratedaccording to the following scheme (6).

wherein R¹, R², R³, R⁴ and X are as noted above.

Preferably, R¹ is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl;most preferably methyl, ethyl or n-propyl.

Preferably, R² and R⁴ are independently hydrogen or halogen or methyl,ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, areeach hydrogen.

Preferably, R³ is C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl,azido, each optionally substituded by one or more halogen, cyano,thiocyano, azido, allylthio, cyclopropyl, acyl and/or phenyl; phenyl:phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl furryl,pyrrole, pyridine, whereby any phenyl moiety may be substituted by oneor more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

Preferably, X is —COOH or —COOMe or —COOEt or —CONH2; most preferably—CONH₂.

The compounds of formula (B) may be isolated in free form or convertedinto their pharmaceuticaly acceptable salts, or vice versa, inconventional manner.

Preferred individual compounds among the compounds having the generalformula (B) have the formulas (B′),(B″) and (B′″).

The compounds of formula (B) are suitable for use in the treatment ofepilepsy and related ailments. According to another embodiment, theinvention therefore concerns a process for preparing a compound having aformula (B)

wherein R¹, R², R³, R⁴ and X are as noted above, via catalyticassymetric hydrogenation of the corresponding compound having theformula (A) as illustrated and defined above. Catalytic hydrogenation isdescribed in many publications or books such as “Synthèse et catalyseasymètriques—auxiliaires et ligands chiraux” Jacqueline Seyden-Penne(1994)—Savoirs actuel, interEdition/CNRS Edition—CH 7.1 “hydrogenationcatalytique” page 287-300.

Unless otherwise stated, references herein to the compounds of generalformula (B) either individually or collectively are intended to includegeometrical isomers i.e. both Z (Zusammen) and E (Entgegen) isomers aswell as enantiomers, diastereoisomers and mixtures of each of these(racemates).

Preferably, the process of the invention concerns the preparation ofcompounds of formula (B) in which R² and R⁴ are hydrogen and X is —COOEor —COOMe or —COOEt or —CONH₂ and R¹ is methyl particularly thosewherein R³ is hydrogen, alkyl (especially propyl) or haloalkenyl(especially difluorovinyl). Best results have been obtained with theprocess for preparing levetiracetam, compound of formula (B) in which R¹is methyl, R² and R⁴ are hydrogen, R³ hydrogen, propyl or difluorovinyland X is —CONH₂.

Generally, this process comprises subjecting to catalytic hydrogenationa compound of formula (A) as described above. Preferably the compound offormula (A) is subjected to asymmetric hydrogenation using a chiralcatalyst based on a rhodium (Rh) or ruthenium (Ru) chelate. Asymmetrichydrogenation methods are described in many publications or books suchas “Asymmetric Synthesis” R. A. Aitken and S. N. Kilényi (1992)—BlackieAcademic & Professional or “Synthesis of Optically active-Amino Acids”Robert M. Willimas (1989)—Pergamon Press.

Rh(I)-, and Ru(ti)-, complexes of chiral chelating ligands, generallydiphosphines, have great success in the asymmetric hydrogenation ofolefins. Many chiral bidentate ligands, such as diphosphinites,bis(aminophosphine) and aminophosphine phosphinites, or chiral catalystcomplexes, are described in the literature or are commerciallyavailable. The chiral catalyst may also be associated to a counterionand/or an olefin.

Although much information on the catalytic activity andstereoselectivity of the chiral catalysts has been accumulated, thechoice of the ligands, the chiral catalysts and reaction conditionsstill has to be made empirically for each individual substrate.Generally the Rh(I) based systems are mostly used for the preparation ofamino acid derivatives, while the Ru(II) catalysts give good toexcellent results with a much broader group of olefinic substrates.Chiral catalyst chelators which may be used in the present invention,are DUPHOS, BPPM, BICP, BINAP, DIPAMP, SKEWPHOS, BPPFA, DIOP, NORPHOS,PROPHOS, PENNPHOS, QUPHOS, BPPMC, BPPFA. In addition to this, supportedor otherwise immobilised catalysts prepared from the above chelators mayalso be used in the present invention in order to give either improvedconversion or selectivity, in addition to improved catalyst recovery andrecycling. Preferred chiral catalyst chelators for use in the method ofthis invention are selected from DUPHOS or Methyl, Diethyl,Diisopropyl-DUPHOS (1,2-bis-(2,5-dimethylphospholano)benzene—U.S. Pat.No. 5,171,892), DIPAMP (Phosphine, 1,2-ethanediylbis((2-methoxyphenyl)phenyl—U.S. Pat. Nos. 4,008,281 and No 4,142,992),BPPM (1-Pyrrolidinecarboxylic acid,4-(diphenylphosphino)-2-((diphenylphosphino)methyl)-, 1,1-dimethylethylester—Japanese patent No 87045238) and BINAP (Phosphine,(1,1′-binaphthalene)-2,2′-diylbis(diphenyl—European patent No. 0 366390).

The structures of these chelators are shown below.

Preferred solvents for use in the method of this invention are selectedfrom, tetrahydrofuran (THF), dimethylformamide (DMF), ethanol, methanol,dichloromethane (DCM), isopropanol (IPA), toluene, ethyl acetate(AcOEt).

The counterion is selected from halide (halogen(−)), BPh₄(−) ClO₄(−),BF₄(−). PF₆(−), PCl₆(−), OAc(−), triflate (OTf(−)), mesylate ortosylate. Preferred counterions for use with these chiral catalysts areselected from OTf(−), BF4(−) or OAc(−).

The olefin is selected from ethylene, 1,3-butadiene, benzene,cyclohexadiene, norbomadiene or cycloocta-1,5-diene (COD).

Using these chiral catalysts, in combination with a range ofcounter-ions and at catalyst-substrate ratios ranging from 1:20 to1:20,000 in a range of commercially available solvents it is possible toconvert compounds of formula (A) into laevorotary or dextrorotaryenantiomers of compounds of formula (B) having high % of enantiomericexcess (e.e.) and in excellent yield, and high purity. Moreover, thisapproach will use standard industrial plant and equipment and have costadvantages.

This asymmetric synthesis process will also be lower cost due to theavoidance of recycling or discarding the unwanted enantiomer obtained bya conventional synthesis process.

Best results have been obtained with the process for preparing(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide or(R)-α-ethyl-2-oxo-1-pyrrolidineacetamide, wherein it comprisessubjecting a compound of formula A′ in the form of a Z isomer or an Eisomer to asynmmetric hydrogenation using a chiral catalyst according tothe following scheme.

In what follows, reference is made particularly to four compounds offormula (A) in which R¹ is methyl, R², R³ and R⁴ are hydrogen and,

for the compound hereinafter identified as precursor Al, X is —COOH;

for the compound hereinafter identified as precursor A2, X is —COOMe;

for the compound hereinafter identified as precursor A2′, X is —COOEt;and

for the compound hereinafter identified as precursor A3, X is —CONH₂.

As will be appreciated by the skilled person, depending on thesubstitution pattern, not all compounds of general formula (A) and (B)will be capable of forming salts so that reference to “pharmaceuticallyacceptable salts” applies only to such compounds of general formulae (A)or (B) having this capability.

The following examples are provided for illustrative purposes only andare not intended, nor should they be construed, as limiting theinvention in any manner. Those skilled in the art will appreciate thatroutine variations and modifications of the following examples can bemade without exceeding the spirit or scope of the invention.

EXAMPLE 1

The preparation of precursor Al was carried out in 70% crude yield byreacting α-ketobutyric acid and pyrrolidinone in refluxing toluene, seeScheme 7. By Z:E, we mean the ratio of Z isomer amount on E isomeramount.

The crude product was recrystallised from acetone in 70% yield. Thegeometry of the double bond was assigned to be Z on the basis ofcorrelation with the ¹H-NMR (Nuclear Magnetic Resonance) spectral datafor known compounds with similar structure.

EXAMPLE 2

Precursor A2 was prepared from Al with diazomethane in THF. It wasobserved that the Z-E ratio changes from 80:1 to 29:1 duringdistillation (see Scheme 8).

The E-isomer of precursor A₂′ has been obtained as shown in Scheme 9from Z-isomer of precursor A₁ with ethanol, dicyclohexylcarbodiimide(DCC) and dimethylaminopyrydine (DMAP).

Esterification of precursor Al was also carried out on a small scalewith PCl₅ in THP then MeOH and gave exclusively the desired methylesters (E:Z=5:1), see Scheme 10.

EXAMPLE 3

Precursor A2 was also prepared by reacting ketobutyric acid methyl esterand pyrrolidinone in refluxing toluene in the presence of a catalyticamount of POCl₃, see Scheme 11.

The esterification of the ketobutyric acid was carried out either withmethanol following a literature method, or with diazomethane. Thesubsequent condensation reaction gave precursor A2 in 60% yield. Thismethod leads to a higher content of E-isomer in comparison to the routevia precursor A1 (Scheme 8). Both routes allow for the preparation ofother ester derivatives of precursor A2.

EXAMPLE 4

Synthesis of the precursor A3 has been effected by reacting the enamideacid with PCl₅ to give the acid chloride and then with gaseous ammoniato obtain the desired enamide amide A3. The product has been confirmedas the Z-isomer.

The crude enamide amide A3 was isolated from the reaction mixture bydissolving it in THF-MeOH and filtering to remove inorganic residues.After evaporation of the solvent a yellow solid was obtained. The crudematerial was purified by dry flash chromatography followed byrecrystallisation from i-PrOH to afford pure material. This procedurehas been successfully applied to produce a single batch of A3 (118 g,54%, >99% by peak area) and is outlined in Scheme 12.

In most cases of the asymmetric hydrogenation of precursors, thecatalyst has been prepared in situ by reacting [Rh(COD)₂]⁺OTf⁻ and therespective chiral ligand in the solvent of choice followed by additionof substrate. Some catalysts are commercially available and these havebeen used without further purification.

EXAMPLE 5

Results from the asymmetric hydrogenation of precursors A1 and A2 usinga number of rhodium based catalyst systems are summarised in thefollowing Table 1. These reactions have been performed with between0.005 mol % and 5 mol % of catalyst and 100 mg or 200 mg of substrate atambient temperature (room temperature: rt) for 24 hours. Reactionconditions such as the H₂ pressure, the kind of solvents, the amount ofprecursor have been modified in order to obtain the optimal conditions.All products have been isolated by evaporation of the solvent from thereaction mixture and analysed without further purification by ¹H-NMRspectroscopy.

The HPLC (High Performance Liquid Chromatography) method for % e.e.determination of the hydrogenation product of precursor Al proveddifficult to develop. Therefore, we converted the crude products intotheir methyl esters using diazomethane in THP solution. The esterderivatives were then analysed using a chiral HPLC method for monitoringthe hydrogenation of enamide ester A2. For the HPLC method, we used aChiracel OD 4.6×250 mm column and IPA/n-hexane (95:05) as eluant.

For the hydrogenated product of precursor A2, the e.e. results have beenobtained by the following chiral HPLC method: Chiralcel OD 4.6×250 mm,IPA-14 exane (5:95 v/v), 205 nm, 1 ml/min at ambient temperature (rt),sample 1 mg/ml, 13 min (S-enantiomer), 16 min (R-enantiomer). Initially,the screening was carried out on 100 mg scale with 5 mol % of catalyst.

The results in % of enantiomeric excess (e.e.) are positive to expressthe percentage of laevorotatory S-enantiomer and negative to express thepercentage of dextrorotatory R-enantiomer.

TABLE 1 St. Am. H2 C.V. e.e. Ma. Mg Catalyst Cou. Loa. Solv. Pres. % %A1 100 (S,S)-Et-DUPHOS OTf(−) 5.0 EtOH 4 100 95 A1 100 (S,S)-BPPM OTf(−)5.0 EtOH 1 68 −64 A1 100 (R,R)-DIPAMP BF4(−) 5.0 DCM 4 100 92 A2 (Z) 200(S,S)-Et-DUPHOS OTf(−) 2.0 EtOH 4 100 98.8 A2 (Z) 200 (S,S)-Et-DUPHOSOTf(−) 0.5 EtOH 4 100 99.1 A2 (Z) 200 (S,S)-Me-DUPHOS OTf(−) 1.0 EtOH 5100 98.9 A2 (Z) 300 (S,S)-Me-DUPHOS OTf(−) 2.0 IPA 5 100 97.9 A2' (E)200 (S,S)-Me-DUPHOS OTf(−) 0.5 EtOH 5 100 99.4 A2' (E) 300(S,S)-Me-DUPHOS OTf(−) 0.5 IPA 5 100 94.0 A2 (E) 4000 (S,S)-Me-DUPHOSBF4(−) 0.025 MeOH 5 100 97.4 A2 (Z) 4000 (S,S)-Me-DUPHOS BF4(−) 0.01MeOH 5 99 99 A2 (Z) 4000 (S,S)-Me-DUPHOS BF4(−) 0.005 MeOH 5 25 97 A2'(E) 300 (S,S)-BPPM OTf(−) 0.5 MeOH 1 100 −99.3 A2' (E) 300 (S,S)-BPPMOTf(−) 0.5 EtOAc 1 100 −95.2 A2 (E) 300 (S,S)-BPPM OTf(−) 0.5 Toluene 1100 −96.2 A2 (Z) 200 (R,R)-DIPAMP BF4(−) 2.0 EtOAc 5 100 94.5 A2 (E) 200(R,R)-DIPAMP BF4(−) 0.5 EtOAc 5 92 96.5

In this table, St. Ma. represents Starting material; Am. representsAmount; Cou. represents Counterion; Loa. represents Loading Mol %; Solv.represents Solvent, H2 Pres. represents H2 pressure (atm); and C.V.represents Conversion.

EXAMPLE 6 Asymmetric Hydrogenation of Precursor A3

Using the same approach as in example 5; a number of rhodium andruthenium catalysts have been screened, see Scheme 13 and Table 2 forrepresentative results.

TABLE 2 Amount H₂ Reaction A3 Loa. Pres. time Reaction Conversion e.e.mg Catalyst metal Cou. mol % solvent volume atm hours temp. % % 100(R)-BINAP Ru OAc(−) 2.5 EtOH 25 4.5 16 rt 100 −82.7 500 (R)-BINAP RuOAc(−) 1.0 EtOH/H₂O 20 4 16 rt 100 −85 5:1 500 (R,R)-DIPAMP Rh BF4(−)0.5 DCM 20 4 18 rt 80-90 90 500 (R,R)-DIPAMP Rh BF4(−) 1.0 DCM 20 4 18rt 100 93 500 (R,R)-DIPAMP Rh BF4(−) 2.5 DCM 20 4 70 rt 100 94.4 500(R,R)-DIPAMP Rh BF4(−) 2.5 EtOH 20 4 70 rt 100 93.8 500 (R,R)-DIPAMP RhBF4(−) 1.0 EtOH 20 4 16 rt 100 85 2000 (S,S)-BPPM Rh OTf(−) 0.5 EtOH 101 40 65-70° C. 100 −7 500 (S,S)-Et-DUPHOS Rh OTf(−) 0.5 DCM 40 4 16 rt100 97 500 (S,S)-Et-DUPHOS Rh OTf(−) 2.5 DCM 40 4 17 rt 100 97

In this table, Cou. represents Counterion; Loa. represents Loading Mol%; H2 Pres. represents H2 pressure; and rt represents room temperature.

As above, the rhodium catalysts have been prepared in situ or purchasedand used without further purification. The ruthenium catalysts wereprepared according to known literature procedures. Most experiments havebeen conducted on a 100 mg to 15 g scale with between 0.001 mol % and 5mol % of catalyst. The crude products have been analysed by ¹H, ¹³C NMRspectroscopy and by chiral HPLC analysis.

EXAMPLE 7 Asymmetric Hydrogenation of Precursor A3 withRh-(Et,Et)-DUPHOS

The results of the hydrogenation of A3 with Rh-DUPHOS catalyst are shownin Table 3. These reactions have been performed in the same way as inexample 5 and 6, with a hydrogen pressure of 4 atmospheres.

Usually, enantioselectivities in the Rh-DUPHOS catalysed hydrogenationsof α-acylaminoacrylic acid derivatives show very little solvent effect.However, it remains impossible to predict a priori what the effect ofthe solvent would be on the enantioselectivity and the rate of thereaction for a given substrate. It has been observed that thehydrogenation of A3 is highly solvent dependant. The non-coordinating,aprotic solvent DCM was found superior. Hydrogenations in proticalcoholic solvents resulted in slower reactions and reduced selectivity.Similarly, reduced conversions were observed in polar aprotic solventssuch as EtOAc and THF, both of which may be expected to coordinate tothe metal and inhibit catalysis. The inhibition by coordinating solventsprobably suggests that A3 is a poorly coordinating substrate, especiallyin comparison to other α-acylamninoacrylic acid derivatives.

Nevertheless, excellent results have been obtained in DCM. As can beseen, enantioselectivities of 97 to 98% e.e. were consistently achievedon 0.5 to 15 g scale in this solvent. Other promising results wereobtained in EtOAc-DCM solvent mixture and in toluene.

TABLE 3 Hydrogenation of A3 with [Rh-CQD-(S,S)-Et DUPHOS]OTf AmountReaction A3 Catalyst solvent time C.V. e.e. mg mol % solvent volume(hours) % % 500 1.0 AcOEt/DCM 30 17 95 96 5:1 500 1.0 DCM 20 17 100 97500 0.5 DCM 30 16 99 98 500 0.5 DCM 40 16 100 97 500 2.5 DCM 40 17 10097 10000 1.0 Toluene 30 65 93 92 500 1.0 Toluene 30 16 95 95

In this table C.V. represents Conversion.

A. Preparation of Precursor A1:(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoic Acid (Precursor A1)

A 1 l flask fitted with a magnetic stirring bar and a Dean-Stark trapwas charged with 2-oxobutanoic acid (25 g. 245 mmol), toluene (500 ml.20 vol) and 2-pyrrolidinone (37.2 ml, 490 mmol, 2 equiv). The reactionmixture was stirred under reflux with azeotropic removal of water viathe Dean-Stark trap for 5.5 hours. The solution was then concentrated toca. 90 ml (3.6 vol) and allowed to cool slowly to ambient temperature.Off-white solid started to come out of solution at around 55° C. Thesolid was filtered, the cake was washed with toluene (2×1 vol) followedby dichloromethane (3×1 vol) and dried on the filter under vacuum for 5nmin to afford crude material (28 g, 70% yield). The crude product wasdissolved in acetone (450 ml, 16 vol) at reflux, cooled slowly toambient temperature and allowed to crystallise over 12 hrs at −15 to−20° C. Pure product was obtained as a white crystalline solid (21 g,51% overall yield).

Melting point (m.p.). 165.5-166° C.

¹H NMR (CDCl₃): δ (chemical shift) 2.13 (5H, doublet (d) and multiplet),2.51(2H, triplet (t)), 3.61(2H,t), 6.27(1H, quadruplet (q)), 8 to 10(1H,broad); signals for E-isomer, δ 1.85(3H, t), 7.18(1H, q).

¹³C NMR(MeOH-d4): δ 14.7, 19.6, 32.1, 51.4, 130.8, 137.7, 166.6, 177.9.

Z:E ratio 149:1, by ¹H NMR.

Thin Layer Chromatography (TLC): SiO₂, Toluene/AcOH/MeOH (4:1:0.5), UVand anisaldehyde stain.

B. Preparation of Precursor A2: Methyl(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoate (Precursor A2)

Precursor A1 (12 g, 71 mmol) was dissolved in THF (240 ml, 20 vol) at0-5° C. A solution of diazomethane in ether (200 ml, ˜78 mmol, 1.1equiv) was added portionwise to the reaction mixture, keeping thetemperature below 5° C. The reaction mixture turned yellow colour withthe last portion of the reagent. This was stirred for additional 30 minat low temperature and then allowed to warm up. The remaining traces ofdiazomethane were destroyed by dropwise addition of very dilute aceticacid in TmF until the yellow solution became colourless. The reactionmixture was concentrated in vacuo and the crude material was distilled(93-94° C., 0.01 mm Hg) to afford pure product (9.44 g. 73%) as acolourless oil, which solidifies on cooling below 10° C.

¹H NMR (CDCl₃): δ 2.0(3H, d), 2.1(2H, m), 2.43(2H, t), 3.54(2H, t),3.76(3H, s), 5.96(1H, q); signals for E-isomer, δ 1.75(3H, d) and7.05(1H, q).

¹³C NMR(MeOH-d4): δ 14.4, 19.7, 32, 51, 52.6, 130.1, 134.4, 165.6,177.4. Z:E ratio 29:1 by ¹H NMR.

C. Preparation of Methyl 2-oxobutanoate.

2-Oxobutanoic acid (15 g) was distilled under-reduced pressure using aKugelruhr apparatus (84° C., 20 mm Hg) to yield 14 g of purifiedmaterial. Distilled 2-oxobutanoic acid (14 g) was dissolved in methanol(anhydrous, 20 ml, 1.4 vol) and dichloroethane (anhydrous, 80 ml, 5.7vol) in the presence of a few drops of ethanesulfonic acid. The reactionmixture was stirred at reflux for 18 hrs under an inert atmosphere. Thenit was allowed to cool down, dried over MgSO₄, filtered and concentratedin vacuo. The crude was purified by distillation (b.p. 76° C., 20 mm Hg)to give a pure product as a colourless oil (7.53 g, 48% yield).

¹H NMR (CDCl₃): δ 0.88(3H, t), 2.66(2H, q), 3.63(3H, s) ref.Biochemistry, 2670, 1971.

D. Preparation of Methyl(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoate (Precursor A2)

A 100 ml flask fitted with a magnetic stirring bar and a Dean-Stark trapwas charged with methyl 2-oxobutanoate (7.5 g, 73 mmol), toluene (50 ml,7 vol) and 2-pyrrolidinone (8.4 ml, 111 mmol, 1.5 equiv) followed bydropwise addition of POCl₃ (1.6 ml, 20 mmol, 0.27 equiv). The reactionmixture was stirred under reflux with azeotropic removal of water viathe Dean-Stask trap for 8 hours. After cooling down the solution waswashed with 10% aq KHSO4 (2×3 vol). The aqueous phase was saturated withNaCl and back extracted with toluene (1×6 vol). The combined organicphase was dried over MgSO₄, filtered and concentrated in vacuo to affordcrude material (7.5 g) as an orange mobile oil. The crude oil wasdistilled (92-94° C., 0.1 mm Hg) and gave pure product (4.7 g, 60%) as acolourless oil.

Z:E ratio 6:1 by ¹HNMR.

E. Preparation of Methyl(E)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoate (Precursor A2)

A dry 100 ml flask fitted with a magnetic stirrer bar was charged withZ-A1 (2 g, 11.8 mmol), ethanol (2.2 ml, 37.3 mmol), tetrathydrofuran(TnHF, 40 ml, 20 vol) and dimethylaminopyridine (DMAP, 150 mg, 1.23mmol) under an nitrogen atmosphere. The reaction mixture was cooled to0° C. before adding dicyclohexylcarbodiimide (DCC, 2.46 g, 11.9 mmol),then heated to ambient temperature. The reaction mixture was stirredvigorously 21 hours. After that hexane (40 ml) was added to precipitatea solid. The precipitate was filtered off and the filtrate wasconcentrated in vacuo to afford 3.03 g of colourless liquid oil. The oilin water (40 ml) was washed with dichloromethane (DCM, 40 ml then 2×20ml), the solvent was dried by Na₂SO₄ and concentrated in vacuo to afford2 g of E-A2 ethyl ester (100% yield).

F. Preparation of Precursor A3:(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenenamide (Precursor A3).

A 20-liter flange flask was set up for stirring under inert atmosphereand was charged with Al (222 g, 1.313 mol, 1 wt) and anhydrous THF (7.0liters, 30 vol). The reaction mixture was allowed to cool below 5° C.and PCl₅ (300 g, 1.44 mol, 1.1 equiv) was added portionwise keeping thereaction temperature below 10° C. The reaction mixture was stirred at −5to 0° C. for one hour, allowed to warm up to 15° C. to dissolve theremaining PCl₅, and then cooled back below 0° C. A condenser filled withdry ice/acetone was fitted and ammonia gas (˜200 g) was bubbled slowlythrough the solution, keeping temperature below 15° C. The suspensionwas stirred for an additional 15 min and the excess ammonia was removedby bubbling nitrogen gas through for several minutes. Methanol (3.7liter, 17 vol) was added, the reaction mixture was refluxed for 1.5 hrs,then cooled below 30° C., filtered, and washed with THF/MeOH (2:1, 600ml, ˜3 vol). The filtrate was evaporated to give a yellow solid. Thismaterial was dissolved in methanol (640 ml, ˜3 vol) and ethyl acetate(440 ml, 2 vol) and purified using dry-flash chromatography (SiO₂, 11wt, 3.4 Kg) with EtOAc/MeOH (6:1) to afford crude product (288 g). Thecrude product was recrystallised from isopropanol (1.9 liters, ˜8.5 vol)to give white crystals (127 g). The solid was dried in vacuum oven atambient temperature for 2 days to yield A3 (118 g, 54%).

¹HNMR (CDCl₃+few drops MeOD): δ 6.75 (1H,q) 3.5 (2H,t) 2.5 (2H,t) 2.15(2H,m) 1.7 (3H,d), traces of impurities.

Elemental analysis (%m/m): C 56.90 (57.13% theory); H 7.19 (7.19%theory); N 16.32 (16.66% theory).

A3 (108 g) was recrystallised again from IPA (1 L, 9.3 vol) to afford afinal batch used in the hydrogenation studies (100 g, 93%).

m.p. 172.0° C.-174.2° C.

Elemental analysis (%m/m): C 56.95 (57.13% theory); H 7.10 (7.19%theory); N 16.38 (16.66% theory).

TLC: SiO₂, Toluene/AcOH/MeOH (4:1:0.5), UV and anisaldehyde stain.

G. Preparation of Chiral Rhodium and Ruthenium Catalysts—Preparation of[Rh(I)L*COD]⁺OTf⁻ (0.15 M Solutions)

[Rh(I)COD₂]⁺OTf⁻ (35 mg, 0.075 mmol) and a chiral ligand L, 0.083 mmol,1.1 equiv) were weighed quickly in air and charged to a flask. The flaskwas sealed with a rubber septum and purged with argon. Anhydrous,degassed solvent (5 ml, 143 vol) was added via the septum. The reactionmixture was degassed (3× vacuum/argon) and stirred for 30 min or untilall solids had dissolved.

H. Preparation of Rh(I)(MeOH)₂[(R)-Binap]

A dry 200 ml Schlenk tube fitted with a magnetic stirrer bar was chargedwith [Rh(I)(nbd)₂]ClO₄ (251 mg, 0.649 mmol) and (R)-Binap (405 mg, 0.65mmol) under an argon atmosphere. Dichloromethane (anhydrous, degassed, 5ml, 20 vol) was added via a syringe and the reaction mixture wasdegassed (3× vacuum/argon). Tetrahydrofuran (anhydrous, degassed, 10 ml,40 vol) was added slowly followed by hexane (anhydrous, degassed, 20 ml,80 vol). The resulting suspension was kept at 0-5° C. for 16 hrs. Thesolvents were decanted under argon and methanol (anhydrous, degassed, 5ml, 20 vol) was added. The Schlenk tube was purged with hydrogen (5×vacuum/hydrogen) and stirred at ambient temperature for 1.5 hrs. Theclear red orange solution was transferred to another Schlenk tube(purged with argon) via a syringe. The catalyst solution was storedunder argon at 0-5° C. and used directly for hydrogenation (Tetrahedron,1245, 1984).

I. Preparation of [RuCl(R)-Binap)(C₆H₆)]⁺Cl⁻

A dry 200 ml Schlenk tube fitted with a magnetic stirrer bar was chargedwith [RuCl₂(C₆H₆)]₂ (0.33 g. 0.66 mmol) and (R)-Binap (0.815 g, 1.3mmol) under argon atmosphere. Degassed anhydrous benzene (20 ml, 60 vol)and ethanol (130 ml, 330 vol) were added and the solution was degassed(3× vacuum/argon). The red brown suspension was heated to 50-55° C. for45 min giving a clear brown solution. This was filtered through a celitepad under argon into another Schlenk tube. The solvents were evaporatedin vacuo to afford the catalyst as a yellow orange solid (1.08 g, 86%)which was stored under argon at 0-5° C. (J. Org. Chem., 3064, 1994).

J. Preparation of [RuCl(R)-Binap)(C₆H₆)]⁺BF₄ ⁻

A dry 100 ml Schlenk tube fitted with a magnetic stirrer bar was chargedwith [RuCl(R)-Binap)(C₆H₆)]⁺Cl⁻ (0.45 g, 0.52 mmol) and degassedanhydrous dichloromethane (20 ml, 44 vol) under argon atmosphere. Theresulting solution was degassed (3× vacuum/argon) and transferred via asyringe to another Schlenk tube containing a degassed suspension ofAgBF₄ (0.15 g, 0.77 mmol, 1.5 equiv) in dichloromethane (10 ml, 22 vol).The mixture was stirred vigorously for 0.5 h and then filtered through acelite pad under argon atmosphere. The filtrate was concentrated invacuo to give the catalyst as a green solid (0.42 g, 88%) which wasstored under argon at 0-5° C. (J.Org.Chem., 3064, 1994).

K. Preparation of Ru(OCOCH₃)₂[(R)-Binap]

A dry 200 ml Schlenk tube fitted with a magnetic stirrer bar was chargedwith [RuCl₂(C₆H₆)]₂ (0.805 g, 1.60 mmol) and (R)-Binap (1.89 g, 3.03mmol, 0.95 equiv) under an argon atmosphere. Anhydrous, degasseddimethylformamide (30 ml, 38 vol) was added and the solution wasdegassed (3× vacuum/argon). The reaction mixture was heated to 100° C.for 10 min to give a dark red solution which was then cooled to ambienttemperature. A degassed solution of sodium acetate (5.2 g, 63.4 mmol, 20equiv) in methanol (50 ml, 60 vol) was charged to the reaction vesseland stirred for 5 min. Degassed water (50 nml, 60 vol) and toluene (25ml, 30 vol) were added and the reaction mixture was stirred vigorouslyfor 5 min. The toluene layer was transferred via a syringe to anotherdry Schlenk tube (purged with argon) and the aqueous phase was extractedwith toluene (2×25 ml). The combined toluene solutions were washed withwater (4×10 ml), the solvent was concentrated in vacuo at 45° C. anddried for 12 hrs under vacuum (0.1 mm Hg). The yellow brown solid wasdissolved in toluene (25 ml) without stirring and hexane (75 ml) wasadded slowly to form a second layer on top. The two phase mixture wasleft to stand at ambient temperature for 7 hrs and then at 0-5° C. for 3days. The catalyst crystallised out. The solvents were removed via asyringe under an argon atmosphere, the solid was washed with hexane (20ml) and dried under vacuum for 2 hrs to give the catalyst as an yellowbrown solid (1.76, 70%) which was stored under argon at 0-5° C. (J.Org.Chem., 4053, 1992).

L. Asymmetric Hydrogenation of Precursors A1, A2, A3.

The asyrmmetric hydrogenation follows the same protocol for eachprecursor. Therefore, only the asymmetric hydrogenation of A3 has beendescribed below.

Asymmetric hydrogenation of precursors A3.

Hydrogenation at Atmospheric Pressure of H₂

A dry 100 ml Schlenk tube fitted with a magnetic stirrer bar was chargedwith the substrate (500 mg, 3 mmol) and purged with argon gas. Degassedsolvent was added via a syringe followed by addition of a catalystsolution (0.5 to 2.5 mol %). The reaction mixture was degassed (3×vacuum/argon) and then purged with hydrogen (5× vacuum/hydrogen) usinghydrogen balloon. The reaction was stirred for 16-65 hrs at ambienttemperature. The hydrogen atmosphere was exchanged with nitrogen and thesolvent was evaporated in vacuo to afford a crude product, which wasanalysed by NMR spectroscopic analysis and chiral HPLC analysis.

Hydrogenation occurred at a pressure of 4 atm.

All manipulations were carried out in an AtmosBagrm (Aldrich ChemicalCo.) under an argon atmosphere. The substrate (500-10000 mg,) was placedin stainless steel high pressure vessel (Vinci Technologies Ltd, France)fitted with a teflon beaker (or glass dish) and a teflon coated magneticstirrer bar. Degassed solvent and a catalyst or a catalyst solution(0.25 to 2.5 mol %) was added. The vessel was sealed and purged withhydrogen by pressurising the vessel to 4.5-5.5 atm and then releasingthe pressure (5 times). Finally, the pressure was adjusted to thedesired level and the reaction mixture was stirred at ambienttemperature for 16-65 hrs. Upon completion the hydrogen atmosphere wasexchanged with nitrogen and the solvent was evaporated in vacuo toafford a crude product, which was analysed by NMR spectroscopic analysisand chiral HPLC analysis.

Purification of final material: Purification of(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam).

Levetiracetam obtained by asymmetric hydrogenation as described above (5g, 98% e.e.) was dissolved in water (20 ml, 4 vol) and extracted withethyl acetate (3×10 ml, 3×2 vol). The organic phase was then backextracted with water (10 ml, 2 vol) and the aqueous phase evaporated toafford a pale yellow solid (4.83 g, 80%). This solid (4 g) was dissolvedin acetone (24 ml, 6 vol) and heated to reflux for one hour. Thesolution was allowed to cool down slowly to 0° C. at a rate of 5-10°C./hr. The crystals were filtered, washed with acetone (1.6 ml, 0.4 vol)and dried to give a white solid (3.23 g, 81%, >99.8% e.e., 54 ppm Rh)

Purification of (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide(Levetiracetam):

Levetiracetam obtained by asymmetric hydrogenation as described above (5g, 98% e.e.) was recrystallised from acetone (30 ml, 6 vol) as above toyield a white crystalline solid (3.94 g, 81%, >99.8% e.e., 52 ppm Rh).This material (3 g) was recrystalilsed again as above to afford a whitecrystalline solid (2.31 g, 77%, >99.8%e.e., 23 ppm Rh).

m.p. 118.4-119.9° C.

What is claimed is:
 1. A compound having a general formula (A), andpharmaceutically acceptable salts thereof,

wherein X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN; R¹ is alkyl, aryl,heterocycloalkyl, heteroaryl, halogen, hydroxy, amino, nitro or cyano;R², R³and R⁴, are the same or different and each is independentlyhydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy,sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonicacid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl, alkoxy,oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, vinyl; R³ is hydrogen, halogen, hydroxy, amino, nitro,cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester,ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl,alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl,alkoxy, oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, (C2-C5)alkenyl, (C2-C5)alkynyl, azido, phenylsulfonyloxy;R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy; andR⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycloalkyl,heteroaryl, alkylthio, arylthio; each alkenyl, azido may independentlybe optionally substituted by one or more halogen, cyano, thiocyano,azido, alkylthi, cyclopropyl, acyl, phenyl.
 2. The compound of formula(A) according to claim 1, wherein R³ is (Cl-C5)alkyl, (C2-C5)alkenyl,(C2-C5)alkynyl, cyclopropyl, azido, phenyl, phenylsulfonyl,phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole orpyridine; each alkyl, alkenyl, alkynyl, cyclopropyl, azido mayoptionally be substituted by one or more halogen, cyano, thiocyano,azido, alkylthio, cyclopropyl, acyl, phenyl; any phenyl moiety may besubstituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro,amino, phenyl.
 3. The compound of claim 1, wherein R¹ is methyl and R²and R⁴ are H, R³ is hydrogen, alkyl or haloalkenyl and X is —CONH₂ or—COOMe or —COOEt or —COOH.
 4. The compound of claim 3 wherein R³ ishydrogen, propyl or difluorovinyl.
 5. The compound of claim 1, which isa Z isomer or an E isomer.
 6. The compound of claim 2, which is a Zisomer or an E isomer.
 7. The compound of claim 3, which is a Z isomeror an E isomer.
 8. The compound of claim 4, which is a Z isomer or an Eisomer.